The present invention is generally directed to cardiac treatment and therapy, and more particularly to a method of treating, preventing, reversing, or ameliorating diastolic dysfuntion.
Hypertension is the most common risk factor for diastolic dysfunction in humans, which can lead to heart failure with preserved ejection fraction (Reference 1). This type of heart failure is increasing, and accounts for significant mortality and healthcare expenditures (References 1 and 2). Current treatments for diastolic dysfunction are inadequate, partially because the mechanism of altered myocardial relaxation is incompletely understood (Reference 3). Nitric oxide (NO) generated by NO synthase (NOS) is a critical modulator of cardiac relaxation (Reference 4), and NO bioavailability is regulated by tetrahydrobiopterin (BH4) (Reference 5).
Under physiological conditions, NOS catalyzes the production of NO from L-arginine to modulate myofilament contractility through mechanisms that are not clear (References 6-9). BH4 depletion, leads to NOS uncoupling (References 5and 10), the production of superoxide instead of NO, and diastolic dysfunction (References 5 and 11). BH4 supplementation reverses these effects. Recently, I have reported that diastolic dysfunction was characterized by altered myofilament properties and by S-glutathionylation of cardiac myosin binding protein-C (MyBP-C) (Reference 12). S-glutathionylation is an oxidative post-translational modification of protein cysteines by the addition of the anti-oxidant tripeptide glutathione (References 13-15). I tested whether the improvement in diastolic dysfunction with BH4 treatment correlated with changes in myofilament properties and in S-glutathionylation of cardiac MyBP-C.